1-acetyl-2-picolinoyl hydrazine



United States Patent 3,357,987 l-ACETYL-Z-PICOLINOYL HY DRAZINE Carl J. Buck, Berkeley Heights, N.J., and Nathan Belcher, East Lyme, Conn assignors to Chas. Pfizer & Co., Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Apr. 6, 1965, Ser. No. 446,100 1 Claim. (Cl. 260-295) This invention relates to a new and useful compound. More particularly it is concerned with a, 1-acetyl-2-picolinoyl hydrazine which has been found to possess valuable properties especially therapeutic properties.

The compound corresponds to the formula:

1-acetyl-2picollnoylhydrazine This compound is effective against Walker 256 tumor system when tested in animals according to the protocol set forth in Cancer Chemotherapy Reports, No. 25, page 12, December 1962 (cf. Table I). It is also effective against that system when variations of that protocol are used for testing purposes.

In accordance with the above-specified protocol healthy non-inbred albino rats weighing an average of 55-65 g. each were selected. The tumor system was obtained from the CCNSC tumor bank, and implanted intramuscularly in the thigh of the rats. The compound was first administered three days after the implant and one dose was administered daily for four consecutive days. The animals were sacrificed on the seventh day and the tumors of the test animals were compared with those of control animals.

In the following table Percent of Inhibition is the difference between 100% and the percentage calculated from the ratio obtained from the tumor weights of treated animals divided by the tumor weights of control animals. In each experiment six rats were used and the compound was administered intraperitoneally to the animals, in

water at neutral pH. Depending upon the dose the volume of solution administered ranged from 0.5 cc. to 1.00 cc. and the concentration of drug from about 4 mg. to about 20 mg./cc.

TABLE I Dose, Route and Survival Percent mgJkg. Schedule Rate Tumor Inhibition 150 LP. 1 x/day 6/6 94 150 LP. 1 x/day 6/6 91 150 LP. 1 x/day 6/6 77 150 LP. 1 x/day 6/6 89 150 LP. 1 x/day 6/6 77 150 LP. 1 x/day 6/6 83 225 LP. 1 x/day 6/6 83 150 LP. 1 x/day 6/6 66 100 LP. 1 x/day 6/6 54 67 LP. 1 x/day 6/6 43 225 LP. 1 x/day 6/6 95 150 LP. 1 x/day 6/6 90 100 LP. 1 X/day 6/6 72 67 LP. 1 x/day 6/6 29 300 LP. 1 x/day 4/6 69 225 LP. 1 X/day 6/6 93 150 LP. 1 X/day 6/6 81 100 LP. 1 x/dey 6/6 75 compound was administered twice daily and various 3,357,987 Patented Dec. 12, 1967 TABLE II Dose, Route and Survival Percent mgJkg. Schedule Rate Tumor Inhibition 300 I.M. BID 6/6 100 225 I.M. BID 6/6 100 150 I.M. BID 6/6 100 100 I.M. BID 6/6 78 300 8.0. BID 6/6 94 225 8.0. BID 6/6 93 150 S.C. BID 6/6 81 100 3.0. BID 6/6 72 300 Oral BID 4/6 95 200 Oral BID 6/6 93 150 Oral BID 6/6 88 Oral BID 6/6 80 50 Oral BID 6/6 56 800 I.M. BID 5/6 99 225 I.M. BID 5/6 96 I.M. BID 6/6 79 100 I.M. BID 6/6 70 5O I.M BID 6/6 70 225 LP BID 6/6 96 When the compound was given intraperitoneally in a single dose, it was well tolerated in dosages up to 225 mg./kg. Even at a dosage of 300 mg./kg., two-thirds of the test animals survived the test period. The compound was also well tolerated when administered twice daily in the variety of modes illustrated in Table II.

The novel compound is prepared by reacting picolinic acid hydrazide with acetic anhydride in a conventional manner in order to acetylate the hydrazine moiety. The following example is a typical example for preparing the novel compound of the present invention.

Example I 5.0 g. (0.0365 mole) picolinic acid hydrazide was dissolved in 30 ml. warm acetic acid, 4 ml. acetic anhydride was added to the solution and the mixture was heated on a steam bath for one hour. The mixture was removed from the heat and 100 ml. benzene was added. The mixture was cooled in an ice bath and with the aid of scratching a white solid crystallized out of the solution.

After two hours cooling the solid was collected and washed with benzene. The product yield was 3.2 g.; M.P. 168-170 C.

The mother liquor was evaporated to dryness at 55 C. under reduced pressure to a solid white residue. The residue was suspended in ethylacetate, filtered, washed with ethylacetate and dried to give an additional 2.3 g. of product; M.P. 167-171 C.

The combined products were recrystallized from methanol-ethylacetate to give 4-5 g. of white needles; M.P. 177.5 C.

We claim: A compound of the formula References Cited UNITED STATES PATENTS OTHER REFERENCES Nielsch, Chem. Abstracts, v01. 53, par. 6913-F (1959). Novotny et al., Chem. Abstracts, vol. 53, par. 10191 WALTER A. MODANCE, Primary Examiner.

A. L. ROTMAN, Assistant Examiner. 

